Amygdala-prefrontal Interactions when Interpreting Ambiguous Facial Expressions of Others Research on facial expressions of emotion has demonstrated that individuals exhibit specific behavioral, physiological, and neural reactions to different facial expressions, and abnormalities of these reactions are closely linked to psychopathology. Of particular importance, it has been suggested that the dynamic interaction between the amygdala and the medial prefrontal cortex (mPFC) plays a crucial role in processing facial expressions. While a significant body of research has focused on facial expressions with clear emotional valence (e.g., fearful faces), studying how people disambiguate emotionally ambiguous facial expressions (e.g., surprised faces) could prove to be a useful approach in assessing amygdala-mPFC interactions. Indeed, previous studies have shown that these regions show an inverse relationship with each other, and that their activity was determined by each individual's evaluation of the surprised faces as being positive or negative (Kim et al., 2003;2004). Based on these findings, the objective of the proposed studies is to elucidate the nature of amygdala-prefrontal interactions in the interpretation of emotionally ambiguous stimuli. To this end, the findings from the proposed studies will contribute to existing knowledge of the amygdala-mPFC circuitry by a) identifying surprised faces that are predominantly positive/negative versus truly ambiguous and their impact on brain activity in Aim 1, b) assessing the amygdala-mPFC interaction by resolving ambiguity in surprised faces through spontaneous and/or induced changes in their perceived valence in Aim 2, and c) establishing genetic and anatomical bases of the observed amygdala-mPFC circuitry, in order to better understand the underlying mechanism that is driving the crosstalk between the two brain regions. Given that the focus of many investigations concerning psychopathological disorders is on the abnormality of the amygdala and the failure of the mPFC to exert regulatory influence on such structures, the proposed studies will help facilitate the study of psychopathology by providing a better understanding of the amygdala-mPFC circuitry through experimental tasks that could be tailored to specific psychopathological disorders. PUBLIC HEALTH RELEVANCE: Amygdala-prefrontal Interactions when Interpreting Ambiguous Facial Expressions of Others Efficient crosstalk between the amygdala and the prefrontal cortex is an essential component of successful emotion regulation (Urry et al., 2006), and conversely, aberrant amygdala-prefrontal circuitry is a hallmark of many major mood and anxiety disorders such as posttraumatic stress disorder (Shin et al., 2005) or major depression (Johnstone et al., 2007). By taking advantage of the inherent emotional ambiguity associated with surprised faces, the tasks in the proposed studies are specifically tailored to tap into and assess the amygdala- prefrontal circuitry. These tasks will be directly applicable to the study of psychopathological groups, allowing the assessment of the amygdala-prefrontal circuitry and its relationship to specific behavioral symptoms, as well as providing a quantifiable index of the functional changes in this circuitry that could be utilized to compare the effectiveness of different treatment types.